1-(p-methoxycinnamoyl)-4-(5-phenyl-4-oxo-2-oxazolin-2-yl)-piperazine as an anti-malarial agent

ABSTRACT

A method of suppressing malarial infections using 1-(pmethoxycinnamoyl)-4-(5-phenyl-4-oxo-2-oxazolin-2-yl)-piperazine as the anti-malarial agent.

United States Patent [191 Geiszler [111 3,821,379 June 28, 1974 l-(P-METHOXYCINNAMOYU-4-(5- PHENYL-4-OXO-2-OXAZOLIN-2-YL)- PIPERAZINE AS ANANTI-MALARIAL AGENT [75] Inventor: Adolph Oscar Geiszler, Mundelein,

Ill.

[73] Assignee: Abbott Laboratories, North Chicago, Ill.

[22] Filed: July 26, 1973 [21'] App]. No.: 382,988

Related US. Application Data [63] Continuation-impart of Ser. No. 263,734, June 8,

1972, abandoned.

[52] US. Cl. 424/250 Primary Examiner-Jerome D. Goldberg Attorney, Agent, or Firm-Robert L. Miblack; Joyce R. Krei; Vincent A. Mallare [57] ABSTRACT A method of suppressing malarial infections using 1- (p-methoxycinnamoyl)-4-(5-phenyl-4-oxo-2-oxazolin- 2-yl)-piperazine as the anti-malarial agent.

1 Claim, No Drawings l P-METHOXYCINNAMO YL )-4-( 5-PHENYL-4- OXO-2-OXAZOLIN-2-YL)-PIPERAZINE AS AN ANTI-MALARIAL AGENT DETAILED DESCRIPTION OF THE INVENTION This invention relates to a method of suppressing ma larial infections using l-(p-methoxycinnamoyl)-4r(5- phenyl-4-oxo-2-oxazolin-2-yl)piperazine as the antimalarial agent.

In treating malaria, it is a primary object to promptly destroy the erythrocytic trophozotes and schizontes of Plasmodium that cause the signs and symptons and pathological effects that characterize the disease. While there are several agents available such as quinine, chloroquine, amodiaquine and chlorguanide, there are problems involved with these agents. Chlorguanide has relatively slow action and resistance has rapidly developed to the drug in some areas as with other of the agentsFurthermore, none of these four drugs have any useful direct action on the gametocytes. Therefore, the search for improved anti-malarial agents continues.

This invention is directed toward the use of one such agent.

propriate compounds for intensive preclinical studies. Utilizing young, non-inbred ICR/AJ Swiss Mice and .-the standard inoculum of Plasmodium berghei KBG 173, it is possible to produce a uniform disease fatal to 100 percent untreated animals within 6 to 8 days with the mean survival time of 6.1 days. Test animals weigh from 18 to 22 grams, but weight variations in any given experimental or control group are confined to 2-3 grams. All animals in any given test are approximately the same age. Animals on test are housed in metal top plastic cages, given a standard laboratory diet and water.

Test animals receive an intraperitoneal injection of 0.5 milliliters of 1:100 dilution of heparinizedhearts blood with a minimum of 90 percent parasitized cells (4 X 10 cells) drawn from donor mice infected one week earlier with Plasmodium berghei. The donor strain is maintained by weekly passages in separate groups of mice inoculated with a 0.5 ml. of 1:500 dilution hyperanized hearts blood.

The test compounds are usually administered after I dissolution or suspension in sesame or peanut oil; A single dose is given subcutaneously 72 hours after the mice are infected with Plasmodium berghei. At this time, a 10 to percent parasitemia has developed; the

The following table summarizes the results of the rodent anti-malarial test for l-(p-methoxycinnamoyl)-4- (5-phenyl-4-oxo-2-oxazolin 2-yl)piperazine.

ANTI-MALARIAL ACTIVITY OF 1-(p-METHOXYCINNAMOYL)-4 (S-PHENYL-4-OXO-2-OXAZOLIN-2-YL)PIPERAZINE Dose IN THE BLOOD INDUCED MOUSE TEST Daily Mortality M'ean Survival Mean Survival mg./kg. (Day after infection/deaths) Time (Drug) Time (Control) 160 Il/0l l2/0l 13/01 [4/0] 15/01 13.0 6.1 320 12/01 13/01 15/01 16/01 19/01 15.0 6.1 640 .6 6.1

The compound useful in the practice of this invention, l-(p-methoxycinnamoyl)-4-(5-phenyl-4-oxo-2- oxazolin2-yl)piperazine, is represented by the following structure: I

In the practice of this invention, 'l-(p-methoxy cinnamoyl )-4-( 5-phenyl-4-oxo-2-oxazolin-2- yl)piperazine is administered to patients suffering from malaria in dosages of from I60 to 640 mg./kg. of body weight daily, preferably in divided dosages, i.e.. three to four times a day. 7

The anti-malarial activity of the compound was first established in the blood induced mouse test which is carried out as follows: this test system is based on comparisons of responses to test compounds by Plasma- 'dz'um berg/lei KBG 173 Malaria in Mice as expressed in mean survival times and the mean survival times of untreated controls. Thus, compounds noted as active produce increases in the survival times of the treated animals that are significant when compared with the survival times of untreated controls. Since an established disease is less sensitive to treatment than a disease in the early stages of development, treatment is withheld until the parasitemia is relatively high in order to assure more reliable assay 9f activity and the selectiqn of ap- The compound useful in the practice of this invention I was prepared as follows: 7

A mixture of 5 g. of p-methoxycinnamic acid, 2 ml. phosphorous trichloride and 25 ml. benzene was stirred and refluxed for 1 hour. The hot mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in 15 ml. N,N-dimethylacetamide and added dropwise to a stirred solution of 3.9 g. of l-(5-phenyl-4- .oxo-2-oxazoIin-2-yl)piperazine and 1.6 g. of triethylamine in N,N-dimethylacetamide. The mixture was stirred at room temperature for 12 hours and filtered. The filtrate is diluted with water and the product collected and recrystallized from 3A ethanol, mp. 21 l-212.

Analysis Calcd. for C H N O C, 68.13; H, 5.72; N. -I0.37

Found: C, 67.87; H, 5.92; N, I053 '1 amount 6f f-Zfimieffioiyirinamofl )-4-( -phenyl-4- oxo-2-oxazolin-2-yl)piperazine, to a patient in need of 1. A method of suppressing malarlal mfectlons com- Such treatment prising adm n EQWEQFQX ffiq y 

